Careful chemical structuring gets insulin through the stomach and into the blood.

Daily jabs of insulin are a painful reality for many with diabetes. That may change if researchers who have successfully tested oral insulin in rats are able to replicate those results in humans.

Nearly 350 million people worldwide suffer from diabetes, and that number is predicted to grow to more than 500 million by 2030. While the more common form, type-2 diabetes, does not always need insulin treatment, nearly a quarter of all diabetes patients depend on insulin injections. Estimated annual sales of oral insulin could be as high as $17 billion.

The benefits of an insulin pill include more than just ease of taking the drug. A pill would mean patients can start taking insulin earlier in the disease's development, which could reduce some of diabetes' secondary complications like blindness and the impaired healing that leads to amputations.

The idea of oral insulin has been around since the 1930s, but the difficulties of making it have previously seemed too large to overcome. First, insulin is a protein—when it comes in contact with stomach enzymes, it is quickly destroyed. Second, if insulin can pass through the stomach safely, it is too big a molecule (about 30 times the size of aspirin) to be absorbed into the bloodstream, where it needs to be in order to regulate blood-sugar levels.

In spite of the difficulties, Sanyog Jain at India’s National Institute of Pharmaceutical Education and Research and his colleagues have been working on delivering insulin in the oral form for many years. Their first fully successful attempt came in 2012, when they developed a formulation that successfully controlled blood-sugar levels in rats. But the materials used were too expensive to consider commercializing the technology.

Now, in a paper published in the journal Biomacromolecules, they have found a cheaper and more reliable way of delivering insulin. They overcome the two main hurdles by first packing insulin into tiny sacs made of lipids (fats) and then attaching to it folic acid (vitamin B9) to help improve its absorption into the bloodstream.

The lipids they use are cheap and have, in the past, been successfully employed to deliver other drugs. They help to protect insulin from being digested by stomach enzymes, which gets it to the small intestine. When the lipid-covered sacs enter the small intestine, special cells on its lining, called microfold cells, are attracted to the folic acid. The folic acid helps activate a transport mechanism that can let big molecules pass through into the blood. The amount of folic acid used in the formulation also appears to be in the safe region.

In rats, Jain’s formulation was as effective as injected insulin, although the relative amounts that entered the blood stream differed. However, it exceeded injected insulin in one key aspect: whereas the effects of an injection subside in 6 to 8 hours, Jain’s formulation helped control blood-sugar levels for more than 18 hours.

The most important part of the research comes after successful testing in animals—the formulation needs to be given to human volunteers. But, Jain said, “at a government institute like ours, we don’t have the sort of money needed for clinical trials.”

He may not have to wait for long, as big pharma companies have been searching for an insulin pill formulation for decades. Two of them, Danish pharma giant Novo Nordisk and Israeli upstart Oramed are in a race to come up with a solution. Google’s venture capital arm, Google Ventures, recently invested $10m in Rani Therapeutics with the hope it will help develop an oral insulin product. Indian firm Biocon also does oral insulin research, and it recently signed an agreement with pharma giant Bristol-Myers Squibb.

Oramed is ahead of Novo Nordisk, with its oral insulin product soon to enter phase-II clinical trials, which is the most advanced stage any oral insulin formulation has ever reached. Oramed chief scientist Miriam Kidron said of Jain’s research: “Most people have the same basic idea to develop an insulin pill, but it's the little differences that will determine ultimate success.”

While Kidron did not reveal Oramed’s formulation, she said, “we attempted liposomal delivery before, just like Jain’s work, but we weren’t successful.” She warned that translating success from rats to humans is very difficult. And she is right—most drugs have a high cull-rate at each stage of their development. Even so, research like Jain’s gives hope that an insulin pill may not remain a dream for long.

This Is Great. The concept is very good. My concerns would be controlling the bioavailability. Many many factors involved that can interfere with or enhance the absorption of oral medications. For most meds, not a huge factor as the therapeutic dose is typically well below the toxic dose. With other drugs, which are termed narrow therapeutic window medications (eg warfarin a valuable blood thinner at low doses, a rat poison at high doses). Insulin is going to have a narrow therapeutic window. Add in the confounding factors of a complex pharmaceutical preparation, varying gut transit times in an individual, varying absorption by different peoples guts and I predict that in practice it will be a difficult drug to use in the clinical setting.

This process confuses me, maybe someone can help. My wife has Type 1 and takes a specific amount of medication based on what she is going to eat (as well as other factors). How would one take an appropriate dose in pill form? The best my mind can come up with is each pill is equivalent of a small number of units, maybe 3-5, then you take X number of pills to reach the necessary dose. Am I missing something?

please! no more pics of hypodermic injections, however well intentioned they may be

This entire article is about developing a replacement for insulin injection therapy. The picture is relevant and appropriate. What else are you going to attach to an article that discusses precisely this method of drug delivery and potential future replacements for it?

This process confuses me, maybe someone can help. My wife has Type 1 and takes a specific amount of medication based on what she is going to eat (as well as other factors). How would one take an appropriate dose in pill form? The best my mind can come up with is each pill is equivalent of a small number of units, maybe 3-5, then you take X number of pills to reach the necessary dose. Am I missing something?

See my post above. The medication might be useful for patients whose diabetes is very stable and who are willing to control their diet very carefully. I don't see this as a home run drug (pharma term for extremely profitable).

This process confuses me, maybe someone can help. My wife has Type 1 and takes a specific amount of medication based on what she is going to eat (as well as other factors). How would one take an appropriate dose in pill form? The best my mind can come up with is each pill is equivalent of a small number of units, maybe 3-5, then you take X number of pills to reach the necessary dose. Am I missing something?

See my post above. The medication might be useful for patients whose diabetes is very stable and who are willing to control their diet very carefully. I don't see this as a home run drug (pharma term for extremely profitable).

Consider the number of patients out there that use insulin at some point in their treatment. Even if the pills are not individually expensive, there will be a lot of patients that can take them.

I would imagine that in addition to a low dose per pill multiplied by instructions to take X pills as needed depending on blood glucose level, patients might also still occasionally use injections to supplement the pill treatment. If the injections were reduced to only occasional use, that would still be a large benefit for many patients.

Another benefit not mentioned here is that insulin in pen form (as pictured in the photo above) has to be kept cold when not being used outside of being carried for a short time in, say, a purse. Insulin in pill form would ideally not need to be kept cold, making it much easier to take doses with you; a bottle of pills could be kept in a purse for months at a time.

I would love to be able to do that. Pill-form insulin not needing refrigeration would be an excellent supplement to a continuous glucose monitor or medications like metformin. Fortunately, I don't need to inject insulin very often, but when I do I am often not at home and the pens are sitting in the fridge, so I have to wait to get a dose. That's frustrating, and hopefully future insulin pills won't be liquigels that also wind up sitting in the fridge.

This process confuses me, maybe someone can help. My wife has Type 1 and takes a specific amount of medication based on what she is going to eat (as well as other factors). How would one take an appropriate dose in pill form? The best my mind can come up with is each pill is equivalent of a small number of units, maybe 3-5, then you take X number of pills to reach the necessary dose. Am I missing something?

See my post above. The medication might be useful for patients whose diabetes is very stable and who are willing to control their diet very carefully. I don't see this as a home run drug (pharma term for extremely profitable).

Consider the number of patients out there that use insulin at some point in their treatment. Even if the pills are not individually expensive, there will be a lot of patients that can take them.

I would imagine that in addition to a low dose per pill multiplied by instructions to take X pills as needed depending on blood glucose level, patients might also still occasionally use injections to supplement the pill treatment. If the injections were reduced to only occasional use, that would still be a large benefit for many patients.

Another benefit not mentioned here is that insulin in pen form (as pictured in the photo above) has to be kept cold when not being used outside of being carried for a short time in, say, a purse. Insulin in pill form would ideally not need to be kept cold, making it much easier to take doses with you; a bottle of pills could be kept in a purse for months at a time.

I would love to be able to do that. Pill-form insulin not needing refrigeration would be an excellent supplement to a continuous glucose monitor or medications like metformin. Fortunately, I don't need to inject insulin very often, but when I do I am often not at home and the pens are sitting in the fridge, so I have to wait to get a dose. That's frustrating, and hopefully future insulin pills won't be liquigels that also wind up sitting in the fridge.

Don't get me wrong. As a health care provider I would LOVE to see an insulin prep (or replacement) that could be taken orally. Adjusting your dose on the fly with this preparation would seem to be problematic. It has to get past the stomach to be absorbed. Gastric emptying time varies of course but 1-2 hours is typical. Anticipating your insulin need ahead of time can be tricky in all but the most stable of diabetics.

As a type 1, I doubt that this will be helpful for me or other type 1s. An insulin pump means many of us have a far better means of controlling blood sugar and only need infusion set changing every 2-3 days. For us an integrated blood sugar monitor + insulin pump will be the next step toward an artificial pancreas. Continuous blood sugar monitors and insulin pumps are already widely used and work very well.

"However, it exceeded injected insulin in one key aspect: whereas the effects of an injection subside in 6 to 8 hours, Jain’s formulation helped control blood-sugar levels for more than 18 hours."

This really does not make any sense. Natural human insulin last around 4 hours. Other designed insulin types are designed to last different lengths of time. So one common type of insulin therapy is to combine a long lasting insulin (up to 24 hours) with a short acting one. The long lasting one covers the baseline insulin needs (basal) and the short term one covered meals (bolus).

Lead picture is misleading. Insulin is injected into fat. Injecting it into muscle (as the person in this stock photo is doing will do bad things to it's effectiveness).

I suspect the author just wanted to use this photo of a nice bum.

I think it's a hip, which is one of the suggested injection sites in the handbook that came with my first pen.

Buran many modern insulin pens are available that can be stored at room temperature for 28 days (this is also the typical useful life of a insulin preparations after being exposed to air in a vial). Check with your pharmacist to see if yours is, or if a suitable replacement is available.

This really does not make any sense. Natural human insulin last around 4 hours. Other designed insulin types are designed to last different lengths of time. So one common type of insulin therapy is to combine a long lasting insulin (up to 24 hours) with a short acting one. The long lasting one covers the baseline insulin needs (basal) and the short term one covered meals (bolus).

Yes, MDI (Multiple Daily Injection) therapy. Also, depending on how you body handles the long-acting you may have 1 or more basal doses of long-acting insulin per day along with any bolus doses of rapid acting insulin. Pumps use only rapid acting insulin and since you can usually program different amounts of basal based on the time of day or even override based on expected activity levels. This aspect and not having to stick yourself 4+ times a day is what makes pumps so awesome! This pill would only be useful for the basal due to it being long acting insulin.

Regarding the comment about differing absorption rates... yes! Even with insulin everyone reacts differently and each patient should, in co-operation with the endocrinologist or CDS/C.D.E., work to develop a plan that works with their body and lifestyle habits. Especially as misuse of rapid acting insulin can lead to coma or death.

The only use for this type of insulin delivery for a Type I diabetic, as far as I can imagine, is as a basal dose. You would still need some form of fast acting insulin for bolus doses before meals. So as far as convenience goes, I don't see this really solving the problem of having to carry insulin and syringes.

please! no more pics of hypodermic injections, however well intentioned they may be

This entire article is about developing a replacement for insulin injection therapy. The picture is relevant and appropriate. What else are you going to attach to an article that discusses precisely this method of drug delivery and potential future replacements for it?

A pill? I dunno, I don't have a problem with the shot picture, but I can understand how some people might be squeamish. I think a pill would be an appropriate image for this particular story.

The only use for this type of insulin delivery for a Type I diabetic, as far as I can imagine, is as a basal dose. You would still need some form of fast acting insulin for bolus doses before meals. So as far as convenience goes, I don't see this really solving the problem of having to carry insulin and syringes.

The most convenient way to go for a diabetes 1 person seems by far seems to be using only fast-acting insulin in a pump. You need the fast-acting for the bolus doses anyway, so not having to mess with different types, easier basal dose adjustment, and general convenience/reduced amount of needle stabbing has to be nice. It doesn't solve the problem of insulin being a sensitive drama queen of a molecule that wilts and dies from any and all combination of temperature, shock, oxygen and age, though.

Of course, it's (at times prohibitively) expensive. Over here it's covered by the national health system, but for the rest of the world, it would be nice if insulin pumps (and fast-acting insulin) could somehow become cheap enough for everyone who would benefit from one.

As unsettling as the injection photo is it's the reality for many diabetics that must stick needles into themselves numerous times a day for both insulin and blood sugar measurements. This would be a wonderful option for a lot of people. I imagine that you could be cautious about sticking to a specific number of carb grams every day base on what you generally eat. People tend to be consistent as far as type of food and quantity whether good or bad. I am not diabetic myself but have a strong genetic predisposition to it. My many diabetic family members will consider it a medical breakthrough. Even though they must inject insulin to stay alive it is something you don't get used to.

Lead picture is misleading. Insulin is injected into fat. Injecting it into muscle (as the person in this stock photo is doing will do bad things to it's effectiveness).

From what I've read about fast-acting and pump needle sites, injecting into muscle will work, though it's not recommended as it will be more painful and could lead to different uptake profiles (as I understood it, the main risk is actually that it could be taken up faster than usual, giving an unexpectedly sudden dip in blood glucose - but don't trust me on that).

This process confuses me, maybe someone can help. My wife has Type 1 and takes a specific amount of medication based on what she is going to eat (as well as other factors). How would one take an appropriate dose in pill form? The best my mind can come up with is each pill is equivalent of a small number of units, maybe 3-5, then you take X number of pills to reach the necessary dose. Am I missing something?

See my post above. The medication might be useful for patients whose diabetes is very stable and who are willing to control their diet very carefully. I don't see this as a home run drug (pharma term for extremely profitable).

Consider the number of patients out there that use insulin at some point in their treatment. Even if the pills are not individually expensive, there will be a lot of patients that can take them.

I would imagine that in addition to a low dose per pill multiplied by instructions to take X pills as needed depending on blood glucose level, patients might also still occasionally use injections to supplement the pill treatment. If the injections were reduced to only occasional use, that would still be a large benefit for many patients.

Another benefit not mentioned here is that insulin in pen form (as pictured in the photo above) has to be kept cold when not being used outside of being carried for a short time in, say, a purse. Insulin in pill form would ideally not need to be kept cold, making it much easier to take doses with you; a bottle of pills could be kept in a purse for months at a time.

I would love to be able to do that. Pill-form insulin not needing refrigeration would be an excellent supplement to a continuous glucose monitor or medications like metformin. Fortunately, I don't need to inject insulin very often, but when I do I am often not at home and the pens are sitting in the fridge, so I have to wait to get a dose. That's frustrating, and hopefully future insulin pills won't be liquigels that also wind up sitting in the fridge.

Don't get me wrong. As a health care provider I would LOVE to see an insulin prep (or replacement) that could be taken orally. Adjusting your dose on the fly with this preparation would seem to be problematic. It has to get past the stomach to be absorbed. Gastric emptying time varies of course but 1-2 hours is typical. Anticipating your insulin need ahead of time can be tricky in all but the most stable of diabetics.

While I do wonder about the delay between taking the pill and seeing the "payload" delivered, I believe it is possible to make a fast-acting medication. I've taken headache pills in the past in gelcap form that killed the headache in 10-15 minutes. That doesn't always happen, but it does seem to indicate that in some cases, there is a fast-acting effect. Alas, I don't remember if I had eaten recently at the time or not.

This is surely something that will be addressed in the research and is one reason why I believe that injectables are not going to completely go away. But there is definitely an application here for, say, taking a dose before you eat so that by the time your glucose levels begin to rise, it will be taking effect. That's already something that's done with injectables -- you inject a dose before you eat based on what your levels are now, and some patients also inject based on what they plan to be eating.

From Facts and Comparisons (medical professional information resource and usually verbatim from the manufacturer package insert which must be provided with every bottle of insulin or each insulin pen device) regarding regular insulin subcutaneous injection.

"Administer by subcutaneous injection in the abdominal wall, thigh, gluteal area, or upper arm. Subcutaneous injection into the abdominal wall ensures a faster absorption than from other injection sites. Injection into a lifted skin fold minimizes the risk of intramuscular injection. Injection sites should be rotated within the same region to reduce the risk of lipodystrophy"

Has someone here not read other posts? Often, insulin therapy is a supplement to metformin and so both treatments are carried out together. Metformin also loses effectiveness over time in some patients, so sometimes metformin therapy is eventually replaced by insulin treatment.

You would think that if metformin, which is a pill, was in itself a sufficient treatment, it wouldn't be necessary to find ways to deliver insulin as a pill as well.

So yes, we have heard of metformin. I'm guessing that you're not diabetic and/or you don't know anybody who is who's talked about their treatments.

Veritas, or anyone else with an idea, is there a reason Sub-Lingual/Buccal/ODT route hasn't been tried? These methods can get some medications into the body very quickly, therefore the therapeutic lag is lessened.

Insulin is injected into fat. Injecting it into muscle (as the person in this stock photo is doing will do bad things to it's effectiveness).

When carrying out the initial stages of regulating a ketoacidotic diabetic, we will sometimes use regular insulin (the fast acting stuff, for those who don't know) by intramuscular injection. The greater vascularity of muscle, and the better perfusion of muscle in patients that are significantly dehydrated (as most are when in a ketoacidotic crisis) means that we get more reliable uptake of the insulin. We also have a much shorter duration of effect (about 2 hours between doses) from the insulin, which means we can titrate dose more effectively.

Once the patient is more stable and has rehydrated, we often switch to subcutaneous regular insulin at the same dose as we have been giving IM, and get durations of effect of 6-8 hours. This is a halfway point towards the use of the longer acting basal insulins (Glargine, Levemir etc).

BTW: I prefer IV regular insulin+dextrose CRI's to stabilise DKA's, but some of our clinicians are more comfortable with the intermittent IM dose regime. And I'm a DVM, not an MD, so things are likely different when treating those fragile humans.